Department of Translational Medicine, Medical College of Xiamen University, Xiamen, 361102, China.
Center for BioMedical Big Data Research, Medical College of Xiamen University, Xiamen, 361102, China.
BMC Genomics. 2018 Jul 16;19(1):538. doi: 10.1186/s12864-018-4906-4.
Esophageal squamous cell carcinomas (ESCC) is the fourth most lethal cancer in China. Previous studies reveal several highly conserved mutational processes in ESCC. However, it remains unclear what are the true regulators of the mutational processes.
We analyzed the somatic mutational signatures in 302 paired whole-exome sequencing data of ESCC in a Chinese population for potential regulators of the mutational processes. We identified three conserved subtypes based on the mutational signatures with significantly different clinical outcomes. Our results show that patients of different subpopulations of Chinese differ significantly in the activity of the "NpCpG" signature (FDR = 0.00188). In addition, we report ZNF750 and CDC27, of which the somatic statuses and the genetic burdens consistently influence the activities of specific mutational signatures in ESCC: the somatic ZNF750 status is associated with the AID/APOBEC-related mutational process (FDR = 0.0637); the somatic CDC27 copy-number is associated with the "NpCpG" (FDR = 0.00615) and the AID/APOBEC-related mutational processes (FDR = 8.69 × 10). The burdens of germline variants in the two genes also significantly influence the activities of the same somatic mutational signatures (FDR < 0.1).
We report multiple factors that influence the mutational processes in ESCC including: the subpopulations of Chinese; the germline and somatic statuses of ZNF750 and CDC27 and exposure to alcohol and tobacco. Our findings based on the evidences from both germline and somatic levels reveal potential genetic regulators of the somatic mutational processes and provide insights into the biology of esophageal carcinogenesis.
食管鳞状细胞癌（ESCC）是中国第四大致命癌症。先前的研究揭示了 ESCC 中几个高度保守的突变过程。然而，目前尚不清楚哪些是突变过程的真正调节因子。
我们分析了中国人群 302 对 ESCC 全外显子测序数据的体细胞突变特征，以寻找突变过程的潜在调节因子。我们根据突变特征确定了三个具有显著不同临床结局的保守亚型。我们的结果表明，不同亚群的中国患者在“NpCpG”特征的活性上存在显著差异（FDR=0.00188）。此外，我们报告了 ZNF750 和 CDC27，其体细胞状态和遗传负担一致影响 ESCC 中特定突变特征的活性：体细胞 ZNF750 状态与 AID/APOBEC 相关的突变过程相关（FDR=0.0637）；体细胞 CDC27 拷贝数与“NpCpG”（FDR=0.00615）和 AID/APOBEC 相关的突变过程相关（FDR=8.69×10）。这两个基因的种系变体负担也显著影响相同体细胞突变特征的活性（FDR<0.1）。
我们报告了多种影响 ESCC 突变过程的因素，包括：中国人群的亚群；ZNF750 和 CDC27 的种系和体细胞状态以及暴露于酒精和烟草。我们基于种系和体细胞水平的证据得出的发现揭示了体细胞突变过程的潜在遗传调节因子，并深入了解了食管癌变的生物学。
